Long non-coding RNAs regulate the hallmarks of cancer in HPV-induced malignancies

https://doi.org/10.1016/j.critrevonc.2021.103310Get rights and content

Highlights

  • LncRNAs are able to regulate the development of the different hallmarks of cancer.

  • LncRNAs are involved in the progression of HPV-induced cancers.

  • Oncoproteins of high-risk HPVs alter the expression levels of several lncRNAs.

  • LncRNAs seem to have potential as biomarkers or therapeutic targets.

Abstract

High-risk human papillomavirus (HPV) is the most frequent sexually transmitted agent worldwide and is responsible for approximately 5% of human cancers. Identifying novel biomarkers and therapeutic targets for these malignancies requires a deeper understanding of the mechanisms involved in the progression of HPV-induced cancers. Long non-coding RNAs (lncRNAs) are crucial in the regulation of biological processes. Importantly, these molecules are key players in the progression of multiple malignancies and are able to regulate the development of the different hallmarks of cancer. This review highlights the action of lncRNAs in the regulation of cellular processes leading to the typical hallmarks of cancer. The regulation of lncRNAs by HPV oncogenes, their targets and also their mechanisms of action are also discussed, in the context of HPV-induced malignancies. Overall, accumulating data indicates that lncRNAs may have a significant potential to become useful tools for clinical practice as disease biomarkers or therapy targets.

Introduction

High-risk human papillomavirus (HPV) infection is responsible for approximately 5% of all human cancers and usually occurs by sexual contact (McBride and Munger, 2018). HPV infection occurs at the basal cell layer of the stratified squamous epithelia of oral, oropharyngeal and ano-genital mucosae and is an established carcinogen of the cervix, head and neck, anus, penis, vulva and vagina (Santos et al., 2018). High-risk HPV infections that escape immune control can persist and a minority of these progress to cancer by a complex process whereby squamous intraepithelial lesions progress to carcinoma in situ and then to invasive squamous-cell carcinoma (zur Hausen, 2002; Smola, 2017; Smola et al., 2017). HPV has a double-stranded circular DNA and belongs to the papillomaviridae family (Handler et al., 2015). These viruses contain genes that code for proteins involved in DNA replication, transcription, or viral assembly: the late genes (L-genes) include L1 and L2, which encode the viral capsid proteins (Brianti et al., 2017) and the early genes (E-genes), namely E1, E2, E4, E5, E6 and E7 which encode the early viral proteins. Expression of proteins E1 and E2 are associated with replication control (Hebner and Laimins, 2006). The viral oncoproteins E5, E6 and E7 stimulate cell growth and are able to block tumour suppressor pathways and apoptosis, and consequently induce DNA damage and genomic instability and also interfere with cell cycle regulation (Brianti et al., 2017; Hebner and Laimins, 2006; Spence et al., 2016; Moody and Laimins, 2010). Moreover, the E6 and E7 oncoproteins are able to promote double strand breaks in both the viral genome and the host’s DNA which facilitate the integration of viral DNA into the host’s genome (Moody and Laimins, 2010; Oyervides-Muñoz et al., 2018; Estevao et al., 2019).

The traits known as hallmarks of cancer are biological competences acquired during the multistep development of human cancers (Li et al., 2016) that include: sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, evading immune destruction, genome instability and mutation and tumour-promoting inflammation. (Hanahan and Weinberg, 2011). Importantly, there exist several long non-coding RNAs (lncRNAs) that seem to regulate the occurrence or the suppression of these hallmarks of cancer, and the deregulation of specific lncRNAs has been associated with cancer progression (Li et al., 2016; Deng et al., 2018; Ali et al., 2018).

LncRNAs are RNA molecules with more than 200 nucleotides in length that have no protein coding potential (Wu and Du, 2017). Many lncRNAs are recognized as important modulators of gene expression in diverse biological functions and cellular contexts, playing an important role at both transcriptional and post-transcriptional levels, and can positively or negatively regulate gene expression (Chen, 2016). The aim of this review is to bring together the current knowledge concerning the actions of lncRNAs to regulate the development of hallmarks of cancer, as well as their potential as biomarkers and as potential therapeutic targets in HPV-induced cancers.

Most lncRNAs are transcribed by RNA polymerase II and undergo transcriptional editing through as splicing, polyadenylation and 5′capping mechanisms, while their ability to form secondary structures enables them to bind various biomolecules including RNA, DNA and proteins (Fig. 1A) (Guttman and Rinn, 2012; Mele et al., 2017; Hadjicharalambous and Lindsay, 2019). LncRNAs are structurally identic to mRNAs, many of them show a poly-A tail and 5′cap (Dahariya et al., 2019). These RNAs contains typical evolutionarily conserved patterns and demonstrate a high level of tissue specificity (Dahariya et al., 2019). Studies have revealed that lncRNAs have a modular architecture and that experimental lncRNA secondary structures described the architecture of each target concerning to the secondary structure motifs, such as internal and terminal loops, helical stems, multi-way junctions and bulges (Chillón and Marcia, 2020). Depending on their genomic position, lncRNAs can be classified into different types such as intronic lncRNAs, sense-overlapping lncRNAs, antisense lncRNAs and long intergenic non-coding RNAs (lincRNAs) (Nie et al., 2015; Jarroux et al., 2017; Rinn and Chang, 2012). Intronic lncRNAs are long noncoding RNAs that overlap with the intronic region of a protein coding gene and their transcription can occur in both directions (sense or antisense) (Jarroux et al., 2017; Rinn and Chang, 2012). Both sense-overlapping and antisense lncRNAs overlap with exons that encode proteins, however they differ in the sense in which they are transcribed (Nie et al., 2015). In contrast, lincRNAs are located in exons between protein-coding genes however, lincRNAs do not intersect with any protein-coding genes (Nie et al., 2015; Jarroux et al., 2017). Many lncRNAs are recognized as important modulators of gene expression in diverse biological functions and cellular contexts, playing an important role at both the transcriptional and post-transcriptional levels, and can positively or negatively regulate gene expression (Chen, 2016). Their numerous roles in the regulation of gene expression can be classified into four types known as their signalling, decoy, guide and scaffold functions (Fig. 1B) (Cheng et al., 2019; Wang and Chang, 2011). The transcription of signal lncRNAs is time- and site- specific in response to various stimuli, so lncRNAs are useful spatiotemporal biomarkers that reflect the activity of cellular signalling pathways and the biological effects of transcription factors (Cheng et al., 2019; Marchese et al., 2017). As decoys, lncRNAs can sequester transcription factors and proteins from chromatin (Cheng et al., 2019; Wang and Chang, 2011; Marchese et al., 2017). LncRNAs, as guides, can recruit ribonucleoproteins complexes to specific chromatin loci, these molecules are capable of recruiting RNA binding proteins to target genes, acting in cis or in trans (Jarroux et al., 2017; Wang and Chang, 2011). As scaffolds, lncRNAs are also able to recruit various proteins to form complexes by binding its multiple effectors at the same time, which can activate or repress the transcription (Cheng et al., 2019; Wang and Chang, 2011). The function of lncRNAs is associated with their subcellular localization, some lncRNAs have the capacity to regulate nuclear functions while others are exported to the cytoplasm to carry out their regulatory role (Fig. 1C) (Chen, 2016). Usually, lncRNAs located in the nucleus modify chromatin by binding epigenetic factors to regulate transcription and are also involved in RNA processing (Hadjicharalambous and Lindsay, 2019; Cheng et al., 2019; Kopp and Mendell, 2018). Cytoplasmic lncRNAs are associated with mRNA stability and translation and can either promote or repress protein expression (Hadjicharalambous and Lindsay, 2019; Kopp and Mendell, 2018). LncRNAs can also act as competing endogenous RNAs (ceRNAs) which regulate microRNAs (miRNAs) expression, affecting the expression of miRNAs’ targets (Cheng et al., 2019). CeRNAs act as sponges of miRNAs increasing the levels of their target mRNA, since miRNAs are involved in the regulation of gene expression through the degradation of their target mRNAs (Sen et al., 2014).

As previously described, lncRNAs are major regulators of gene expression at many levels and therefore, are able regulate several cell signalling pathways (Chen, 2016). The aberrant expression of some lncRNAs is linked with the process of tumorigenesis (Bhan et al., 2017). Many lncRNAs are abnormally expressed in diverse tumours and some appear to be related to a specific type of cancer (Bhan et al., 2017). Thus, lncRNAs can act as oncogenes and also as tumour suppressors (Goodall and Wickramasinghe, 2021). However, based on the complexity of the lncRNAs mode of action some of them could have multiple function, as for example, lincRNA-p21 which was first described as a p53-induced tumour suppressor (Huarte et al., 2010) and later reported to be involved in hypoxic cells process by protecting the hypoxia-inducible factor 1α from ubiquitylation, and thus contributing to tumorigenesis (Goodall and Wickramasinghe, 2021; Yang et al., 2014). The lncRNA LINKA (also named LINC01139) has an oncogenic role, through the downregulation of proteins involved in the antigen presentation machinery, enabling the immune escape (Hu et al., 2019). NEAT1 is a lncRNA extremely upregulated in numerous types of cancer, it acts as a ceRNA sponging miRNAs with tumour suppressor functions. Consequently, miRNAs cannot degrade or silence their frequently oncogenic targets, enhancing carcinogenesis (Klec et al., 2019). PVT1 is also a lncRNA characterized as an oncogene, it was overexpressed in diverse types of cancers and stabilizes MYC which had crucial roles in the response to proliferative and growth signals (Tseng et al., 2014). Recent studies have demonstrated that MALAT1 contributes significantly to cancer development and progression by regulating diverse molecular signalling pathways including MAPK/ERK (Liu et al., 2018a), PI3K/AKT (Dong et al., 2015), WNT/β-catenin (Liang et al., 2017), and NF-kB (Zhao et al., 2016) promoting alterations in proliferation, cell cycle, angiogenesis, cell death, migration, invasion, immunity and tumorigenicity (Li et al., 2018a). LncRNAs can also act as tumour suppressors, like LINC00261, which has been found to be downregulated in multiple cancers, compared with normal tissue samples (Goodall and Wickramasinghe, 2021). This lncRNA was able to block cellular proliferation by activating the DNA damage signalling pathway leading to cellular division arrest (Goodall and Wickramasinghe, 2021; Shahabi et al., 2019). Characterizing the mechanisms through which lncRNAs promote tumorigenesis, tumour growth and progression are essential for developing novel cancer therapies which target these altered RNAs (Goodall and Wickramasinghe, 2021).

Some lncRNAs have shown potential as biomarkers for diagnosis and prognosis and as therapeutic targets, for example, the prostate cancer antigen 3 (PCA3) which is a Food and Drug Administration (FDA) approved lncRNA biomarker for prostate cancer detection (Sharma and Munger, 2020a; Deng et al., 2017; Hessels et al., 2003). PCA3 is a specific marker which is overexpressed in prostate cancer and can be easily detected by urine collection (Deng et al., 2017; Hessels et al., 2003). LncRNA prostate cancer-associated non-coding RNA transcript 18 (PCAT-18) is specific for prostate tissue, and is upregulated in prostate cancer. This RNA can be detected in plasma and its expression is correlated with progression of prostate cancer. The silencing of PCAT18 activated caspase activity which consequently inhibited cell proliferation, migration, and invasion suggesting that this lncRNA could be a potential therapeutic target and biomarker for metastatic prostate cancer (Crea et al., 2014). In tissue samples of patients with early-stage non-small cell lung cancer the lncRNA MALAT1 is also used to predict patient survival and tumour metastasis (Ji et al., 2003), this lncRNA is also correlated with prostate cancer development (Ren et al., 2013). The lncRNA urothelial carcinoma associated 1 (UCA1) is a key player in resistance to anticancer drugs such as, imatinib, cisplatin and gemcitabine in several types of cancer (Wang et al., 2017). In ovarian cancer, it was demonstrated that the overexpression of this lncRNA in ovarian cancer tissues was associated with bad response to platinum-based chemotherapy (Wang et al., 2017; Zhang et al., 2016a). Moreover, the levels of the lncRNA P21‐associated ncRNA DNA damage activated (PANDAR), in gastric cancer tissue samples, allow the distinction of chemoresistance group from the chemosensitive group among patients with gastric cancer (Liu et al., 2018b). Therefore, PANDAR might be a promising therapeutic response predictor. The EGFR-AS1 lncRNA also seems to be an important biomarker to predict the therapeutic response to the erlotinib which is an anticancer drug able to target the epidermal growth factor receptor (EGFR). Nath et al. demonstrated that erlotinib-resistant lung cancer cell lines expressed low levels of EGFR-AS1 (Nath et al., 2019). This lncRNA was also able to identify cervical cancer patients whose benefit from erlotinib therapy, as these patients showed higher levels of this lncRNA. However, in HPV16 E6/E7-transformed cells the levels of EGFR-AS1 were lower than in normal cells which may predict a worse response to the erlotinib therapy (Sharma and Munger, 2020a).

These are examples of some lncRNAs with significant potential as biomarkers and therapeutic targets, which may become useful tools for clinical practice. However, further validation studies prior to clinical implementation are necessary. Additional examples related to HPV-induced malignancies will be further explored in the following sections.

The E6 and E7 early proteins are oncoproteins and the main mediators in the carcinogenic process induced by high-risk HPV, due to their interactions with several cellular targets including tumour suppressors (Estevao et al., 2019; de Sanjosé et al., 2018; Boulet et al., 2007). The major function of the oncoprotein E6 is binding with the tumour suppressor p53, a DNA-binding protein that is expressed to avoid inappropriate DNA replication and to respond to DNA damages leading to cell cycle arrest or apoptosis (de Sanjosé et al., 2018; Boulet et al., 2007). The binding between E6 and p53 proteins, is achieved by E6-associated protein (E6-AP) which is a ubiquitin-ligase that enables the proteolysis of p53 through the recruitment of the ubiquitin complex (Boulet et al., 2007). Additionally, E6 oncoproteins enhance mitotic activity by inhibition of degradation of SRC-family kinases by E6-AP (zur Hausen, 2002; Boulet et al., 2007). This oncoprotein also interacts with the pro-apoptotic protein BAK resulting in resistance to apoptosis and in chromosomal instability (zur Hausen, 2002; Jackson et al., 2000). Besides, the high-risk E6 protein activates telomerase, increasing telomerase activity through transcriptional activation of the human telomerase reverse transcriptase (hTert) gene, encoding the telomerase catalytic subunit and resulting in tumour growth and cell immortalization (Boulet et al., 2007; Cong et al., 2002).

The E7 oncoprotein has pRB as the main target and is able to inactivated it, thereby facilitating the progression to the S-phase of the cell cycle. In normal cells, pRB is hypophosphorylated binding to E2F transcription factors that form complexes able to function as transcriptional repressors (Boulet et al., 2007). However, when E7 interacts with pRB, the binding between this protein and the transcription factor E2F is inhibited, which results in cell cycle progression (Boulet et al., 2007; Fehrmann and Laimins, 2003). Moreover, E7 stimulates the S-phase genes cyclin E and cyclin A decreasing the inhibitory functions of cyclin-dependent kinase inhibitors (CKIs) which is a major factor in growth stimulation of HPV-infected cells (Boulet et al., 2007; Molijn et al., 2005). E7 is also able to reduce the major histocompatibility (MHC) abundance at the cell surface contributing to immune escape (Doorbar et al., 2015).

Expression of the early proteins E1 and E2 is associated with viral replication control and E2 is also crucial in the transcriptional regulation of E6 and E7. Moreover, E4 protein plays an important role in viral escape from the epithelial surface and transmission (Estevao et al., 2019; Doorbar et al., 2015; Egawa et al., 2015).

Furthermore, the oncoprotein E5 can promote the proliferation of cancer cells through the formation of complexes with growth factor receptors such as with the Epidermal Growth Factor Receptor (EGFR) (Estevao et al., 2019). This protein is also able to inhibit apoptosis, contribute to immune escape and promote the accumulation of mutations (Estevao et al., 2019).

High-risk HPV is the cause of almost all cervical cancer and is responsible for a considerable part of the other anogenital cancers such as vulva, vagina, anus and penis (de Martel et al., 2017; Medeiros-Fonseca et al., 2020). Concerning head and neck lesions, approximately 30 % of oropharyngeal cancers, which include those arising from the tonsils and base of tongue, are caused by high-risk HPV (de Martel et al., 2017; Mestre et al., 2020).

Regarding other cancers potentially related to high-risk HPV, oesophageal cancer, particularly oesophageal squamous cell carcinoma, has been proposed to be correlated with HPV infection (Santos et al., 2018; Guo et al., 2016; Liyanage et al., 2013). The role of HPV in lung cancer remains a matter of debate, but HPV16 oncoproteins seem to have an important role in non-small cell lung cancer progression (Santos et al., 2018; de Freitas et al., 2016; Zhai et al., 2015).

HPVs, like other viruses, are able to intensely alter the expression profile of host cellular lncRNAs (Sharma and Munger, 2020a; Carnero et al., 2016; Imam et al., 2015). There are “pro-viral” lncRNAs that enhance the invasion of the virus and the reprogramming of the host cell in order to sustain the viral life cycle. Conversely, there are also “anti-viral” lncRNAs that regulate the innate and adaptive immune responses to eradicate HPV (Sharma and Munger, 2020a). Numerous studies have focused on the clinical consequences of the lncRNA expression changes in HPV-related cancers. Some of these studies, demonstrate that the oncoproteins E6 and/or E7 act as regulators of some lncRNAs, including PVT1, MALAT1, SNHG12, lnc−CCDST, LINC01101 and LINC00277 as will be further explained in the following sections (Sharma and Munger, 2020a). Sharma et al. demonstrated that the expression of the lncRNA cervical carcinoma expressed PCNA regulatory (CCEPR) was upregulated in HPV16 E6/E7 cervical cancer cell lines and they also determined that CCEPR was predominantly expressed in the nucleus, enabling gene expression through transcriptional and/or epigenetic regulation (Sharma and Munger, 2020a, 2018). Concerning the lncRNA HOTAIR, the same authors observed lower levels of this lncRNA in HPV16 E6/E7 cervical cancer cell lines (Sharma and Munger, 2020a) and in silico analysis predicted that HPV16 E7 binds HOTAIR (Sharma et al., 2015). HOTAIR has been described to recruit two different chromatin silencing complexes: polycomb repressive complex 2 (PRC2) at its 5’ end and histone lysine demethylase KDM1A (LSD1)-associated complexes at its 3’ end serving as a scaffold for at least two dissimilar histone modification complexes (Tsai et al., 2010). Thus, the binding of the oncoprotein E7 may impede the capacity of HOTAIR to interact with PRC2 contributing to the ability of HPV16 E7 to cause de-repression of polycomb regulated genes (Sharma and Munger, 2020a; McLaughlin-Drubin et al., 2008). The EZH2-Binding lncRNA in cervical cancer (EBIC) also named thymopoietin pseudogene 2 (TMPOP2), may promote the motility and invasion of cervical cancer cells via repression of E-Cadherin (Sun et al., 2014). The experiments of Sharma et al. revealed an increase of TMPOP2 expression by HPV16 E6/E7 suggesting that the expression of this lncRNA was regulated by those oncoproteins (Sharma and Munger, 2020a; He et al., 2019). Moreover, TMPOP2 was reported to increase the expression of HPV E6/E7 by sponging miR-375 and miR-139, which have been previously reported to target HPV E6/E7 mRNA (Jung et al., 2014; Sannigrahi et al., 2017). The colorectal neoplasia differentially expressed (CRNDE) lncRNA is overexpressed in cervical cancer tissues being correlated with poor clinical outcome and tumour size. Then, RNAseq results suggested that CRNDE overexpression was driven by HPV16 E6/E7 expression (Harden et al., 2017). It is also plausible that the HPV oncoproteins may have a crucial role in the regulation of epithelial differentiation at least in part by controlling the expression of the pro-differentiation lncRNA (TINCR) and/or the anti-differentiation lncRNA (DANCR) (Sharma and Munger, 2020a). In particular, it was found that TINCR levels were reduced by HPV16 E6/E7, while DANCR levels were increased (Harden et al., 2017).

Section snippets

Resisting cell death

Programmed cell death by apoptosis is one of the most important biological processes to avoid the development of cancer and the ability to escaping programmed cell death allows the progression of early neoplastic cells towards high-grade lesions (Hanahan and Weinberg, 2011). In this context, specific lncRNAs are able to promote the proliferation and inhibit the apoptosis of cancer cells (Aalijahan and Ghorbian, 2019). Zhang et al. found high levels of the lncRNA ovarian cancer-specific

LncRNAs as potential biomarkers or therapy targets in HPV-induced cancers

As discussed in the previous sections, lncRNAs are crucial in the regulation of the hallmarks of cancer (Li et al., 2016; Zhang et al., 2019a; Jin et al., 2019). Some of these molecules have also shown potential as biomarkers for diagnosis and prognosis and as therapeutic targets in the various types of HPV-induced cancers (Ma et al., 2017; Jiang et al., 2014). Determining novel biomarkers for the early detection of these diseases remains challenging (Iancu et al., 2017), but promising recent

Conclusions

Non-coding RNAs have shown to regulate signalling pathways involved in the pathogenesis of several types of cancers, including HPV-induced cancers. However, most studies focus on the potential of microRNAs, and studies concerning the role of lncRNAs remain scarce. The present review brings together and discusses recent data showing that many lncRNAs are critically involved in either promoting or countering the hallmarks of malignancy observed in HPV-induced cancers (Fig. 2). Importantly, the

Author contributions

Conceptualization, T.R.D, J.M.O.S. and R.M.; investigation, T.R.D and J.M.O.S.; writing—original draft preparation, T.R.D.; writing—review and editing, J.M.O.S., R.M.G.d.C., and R.M.; figure drawing, T.R.D.; supervision, R.M.G.d.C. and R.M. All authors have read and agreed to the published version of the manuscript.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgements

This study was supported by the Portuguese League Against Cancer–Regional Nucleus of the North (Liga Portuguesa Contra o Cancro–Núcleo Regional do Norte); by the Research Center of the Portuguese Oncology Institute of Porto (project no. PI86-CI-IPOP-66-2017); and by Base Funding-UIDB/00511/2020 of the Laboratory for Process Engineering, Environment, Biotechnology, and Energy—LEPABE—funded by national funds through the FCT/MCTES (PIDDAC). Joana M.O. Santos is supported by a PhD fellowship

Tânia R. Dias received her BSc in Biochemistry from the Faculty of Sciences of the University of Porto and Abel Salazar Institute for the Biomedical Sciences (ICBAS) in 2019. Currently, she is a master student in the Molecular Medicine and Oncology master programme from the Faculty of Medicine of the University of Porto and she is developing her MSc thesis at the Molecular Oncology and Viral Pathology Group from the IPO-Porto Research Center. Her research interests include human papillomavirus,

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    Tânia R. Dias received her BSc in Biochemistry from the Faculty of Sciences of the University of Porto and Abel Salazar Institute for the Biomedical Sciences (ICBAS) in 2019. Currently, she is a master student in the Molecular Medicine and Oncology master programme from the Faculty of Medicine of the University of Porto and she is developing her MSc thesis at the Molecular Oncology and Viral Pathology Group from the IPO-Porto Research Center. Her research interests include human papillomavirus, non-coding RNAs, long non-coding RNAs, cancer, premalignant lesions, cancer biology, cancer cachexia.

    Joana M.O. Santos received her BSc degree in Biology from the Faculty of Sciences of the University of Porto in 2014, and her MSc degree in Oncology from the Abel Salazar Institute of Biomedical Sciences of the University of Porto in 2016. Currently, she is a PhD student in the doctoral programme in Biomedicine from the Faculty of Medicine of the University of Porto and she is developing her PhD thesis at the Molecular Oncology and Viral Pathology Group from the IPO-Porto Research Center. Her research interests include human papillomavirus, non-coding RNAs, microRNAs, cancer, premalignant lesions, cancer biology, cancer cachexia and inflammation.

    Rui M. Gil da Costa graduated as a veterinary surgeon in 2003 from the University of Trás-os-Montes and Alto Douro, Portugal. After practicing as an official veterinary surgeon in the United Kingdom, he took an MSc degree in Oncology, a Residency in Veterinary Pathology and a PhD in Biomedical Sciences at the University of Porto's Abel Salazar Institute for Biomedical Sciences. He first undertook post-doctoral studies at the University of Porto Faculty of Engineering and the Portuguese Institute of Oncology and then with Dr. Peter Nelson at the Fred Hutchinson Cancer Research Center. He is now a Senior Visiting Professor at the Federal University of Maranhão (São Luís, Brazil) and remains a collaborating member of three Portuguese research groups at the University of Porto, the Portuguese Institute of Oncology and the University of Trás-os-Montes and Alto Douro. His work, largely focused on translational cancer research, originated 79 indexed scientific papers (Scopus) with h index = 18, and his research interests are presently centered on basic and translational research on urogenital malignancies, especially HPV-related cancers.

    Rui Medeiros is the Head at the Molecular Oncology and Viral Pathology at the Portuguese Oncology Institute of Porto (IPO Porto) working in the field of oncogenomics and therapeutics. He has authored (co) 400 articles, targeting the identification cancer associated-molecular biomarkers towards a personalized early screening and diagnosis and effective management of patients with precision medicine (orcid.org/0000-0003-3010-8373, h-index 38–48). Rui Medeiros is Professor of Pharmacogenomics at Medicine and Molecular Oncology or Oncology MSc/PhD Programmes.

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